RAD51 is essential for DNA repair, proliferation and survival of cells. RAD51 protein level is elevated in many cancer cells, contributing to their resistance to chemotherapy and the continuous cell proliferation (Flygare et al., 2001, Exp. Cell Res. 268:61-69; Chen et al., 1999, J. Biol. Chem. 274:32931-32935; Chen et al., 1998, Proc. Natl. Acad. Sci. USA 95:5287-5292; Klein, 2008, DNA Repair 7:686-693; Maacke et al., 2000, Oncogene 19:2791-2795; Qiao et al., 2005, Br. J. Cancer 93:137-143; Raderschall et al., 2002, Cancer Res. 62:219-225; richerdson et al., 2004, Oncogene 23:546-553; Robu et al., 2001, Proc. Natl. Acad. Sci. USA 98:8211-8218; Slupianek et al., 2001, Mol. Cell 8:795-806). Targeting RAD51 is therefore an attractive strategy for treating difficult-to-treat cancers, such as triple negative breast cancers, which are often easy to metastasize and difficult to treat (Hudis et al., 2011, Oncologist 16:1-11; Peddi et al., 2012, Int. J. Breast Cancer 2012:1-7) as they known to be resistant to most common therapeutics. Recently, a small molecule RAD51 inhibitor (Zhu et al., 2013, EMBO Mol. Med. 5:1-13), designated as IBR2, was identified and validated. RAD51 was rapidly degraded in IBR2-treated cancer cells, and the homologous recombination repair was impaired, subsequently leading to cell death. However, the IC50 values of IBR2 were only in the range of 12-20 μM for most tested cancer cell lines.
There is a need in the art for novel RAD51 inhibitors with improved potency. The present invention addresses this unmet need.